Covalent stapling of peptides is a technique that has been used to increase the proteolytic stability of peptides with the aim of increasing serum half life of peptide pharmaceuticals. Previous work by our lab on the WW domain of the human protein Pin1 has accomplished a similar goal of increasing stability by using Polyethylene Glycol (PEG), a bioconjugate often coupled onto peptides as a chain to stabilize them. We have found that targeted coupling of PEG increases both proteolytic and conformational stability in certain sites. When used as a staple connecting positions where individual PEG chains are shown to be stabilizing, PEG confers even greater proteolytic and conformational stability than the individual chains. The application of PEG as a staple yielding increased conformational stabilization has been further demonstrated in the larger protein SH3.<br/>We have further developed this technique by using aqueous phase coupling via copper catalyzed click chemistry. This allows additional possibilities for synthesis and has demonstrated increased conformational stabilization in the WW domain compared to previously used on-resin olefin metathesis. Additional manipulations of this motif exhibit properties that hold promise to benefit the pharmacokinetics and in vivo stability of peptide and protein based pharmaceuticals.

Variations on peptide stapling using PEG

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.